ES2152222T4 - SULFONAMIDS, ITS PREPARATION AND ITS USE AS A MEDICINAL AND INTERMEDIATE. - Google Patents

Abstract

THE NEW SULFONAMIDS, OF FORMULA I, IN WHICH THE SYMBOLS R1 DESCRIPTION, AND THE SALTS DERIVED FROM IT CAN FIND USING AS ACTIVE SUBSTANCES FOR THE OBTAINING OF REMEDIES FOR THE TREATMENT OF CIRCULATION DISEASES, ESPECIALLY HYPERMONOSMARK, VETRAULES ANGINA PECTORIS.

Description

Sulfonamides, their preparation and their use as Medication and intermediate.

The present invention relates to new sulfonamides and their use as medicines. In particular, the invention refers to new compounds of formula

one

in where

R1 means hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkylthio from 1 to 7 carbon atoms, halogen or trifluoromethyl;

R2 means hydrogen, halogen, alkoxy from 1 to 7 carbon atoms, trifluoromethyl or -OCH 2 COOR a;

R 3 means hydrogen, halogen, alkyl from 1 to 7 carbon atoms, alkylthio from 1 to 7 carbon atoms, trifluoromethyl, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 7 carbon atoms or trifluoromethoxy,

R 2 and R 3 together mean butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

R 4 means hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 at 7 carbon atoms, alkylthio of 1 to 7 atoms of carbon-alkyl of 1 to 7 carbon atoms, hydroxyalkyl of 1 to 7 carbon atoms, hydroxyalkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 atoms of carbon-alkyl of 1 to 7 carbon atoms, hydroxyalkoxy of 1 to 7 carbon atoms-alkyl from 1 to 7 carbon atoms, hydroxyalkoxy from 1 to 7 atoms of carbon-alkoxy of 1 to 7 carbon atoms, alkylsulfinyl of 1 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenylpropyl, aminoalkyl of 1 to 7 carbon atoms, alkylamino of 1 to 7 atoms carbon-alkyl of 1 to 7 carbon atoms, dialkylamino of 1 to 7 carbon-alkyl atoms of 1 to 7 carbon atoms, amino, alkylamino of 1 to 7 atoms of carbon, dialkylamino of 1 to 7 carbon atoms, arylamino, aryl, arylthio, aryloxy, aryl-alkyl of 1 to 7 atoms of carbon,

wherein aryl represents unsubstituted phenyl or alkyl substituted phenyl of 1 to 7 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 carbon atoms, carboxyl or halogen, unsubstituted heterocyclyl of the group of 2-furyl, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 2,3, or 4-pyridyl-N-oxide, 1,2- or 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indole, purinyl, quinolyl, isoquinolyl, quinazolyl or heterocyclyl as defined above, substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, halogen, aryl or aryl-alkyl of 1 to 7 atoms of carbon;

R 5 hydrogen, alkyl of 1 to 7 atoms of carbon, alkanoyl of 1 to 7 carbon atoms, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl, wherein heterocyclyl is chosen from 2-fury without replacing, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 1,2- or 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, quinazolyl or heterocyclyl as defined above, substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, halogen, phenyl or aryl-alkyl of 1 to 7 carbon atoms or tetrahydropyran-2-yl;

R 6 to R 9 means hydrogen, halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, 1 to 7 carbon alkoxy, alkylthio of 1 to 7 atoms of carbon, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or alkyloxy of 1 to 7 carbon atoms carbonyloxy;

R 7 together with R 6 or R 8 means butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy;

Z means -O-, -S-, vinyl, -CO-, -OCHR 10 - or -SCHR 10;

R 10 means hydrogen or alkyl of 1 to 7 carbon atoms;

X and Y mean each independently among themselves, O, S or NH; or YR 5 also means alkylsulfinyl of 1 to 7 carbon atoms;

R a, R b, R c and R d each independently mean each other hydrogen or alkyl of 1 to 7 carbon atoms
no; or

R c and R d together mean methylene, ethylene or isopropylidene; Y

n means 1, 2 or 3,

and you leave the same.

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The expression "from 1 to 7 carbon atoms" used means groups of 1 to 7 carbon atoms, of preference of 1 to 4 carbon atoms. The alkyl, alkoxy groups and alkylthio as well as alkyl groups as group components Alkanoyl can be straight or branched chain. Methyl, ethyl, propyl, isopropyl, butyl, sec.butyl and tert.butyl are examples of these alkyl groups. Halogen, means fluorine, chlorine, bromine and iodine, with chlorine being the most preferred. Cycloalkyl radicals, they mean 3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. Examples of aryl radicals they are the phenyl and substituted phenyl radicals, the halogen being, alkyl of 1 to 7 carbon atoms, alkoxycarbonyl of 1-7 atoms of carbon and trifluoromethyl substituents to consider especially. Examples of heterocyclyl radicals especially substituted are, e.g. ex. by alkyl of 1 to 7 carbon atoms, 1 to 7 carbon alkoxy, halogen, aryl, aryl-alkyl of 1 to 7 carbon atoms as or disubstituted, unsubstituted heterocyclic radicals, mono or bicyclic, 5 and 6 members, with oxygen, nitrogen or sulfur as heteroatom, such as 2- and 3-furyl, pyrimidinyl, 2-, 3 and 4-pyridyl and pyridyl N-oxide, 1,2- and 1,4-diazinyl, morpholino, 2- and 3-thienyl, isoxazolyl, oxazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl and quinazolyl.

The compounds of formula I mentioned previously they are inhibitors of endothelin receptors. They can therefore be used for the treatment of disorders associated with endothelin activities, especially circulation disorders such as hypertension, ischemia, angiospasms and angina pectoris.

A preferred group of compounds within the formula I comprises those in which Z is -O- and also, those in which R 6 is alkoxy of 1 to 7 carbon atoms, especially methoxy, and R 7, R 8 and R 9 mean hydrogen; or R 6 and R 8 mean hydrogen, R 7 means alkoxy of 1 to 7 carbon atoms, especially methoxy, and R 9 means halogen, especially chlorine.

Preferred R 1 and R 2 substituents they are hydrogen and the preferred substituents R 3 are alkyl of 1 to 7 carbon atoms or together with R2 methylenedioxy. The Preferred R 4 substituents are hydrogen, 2-pyrimidinyl, 2- and 3-furyl, 2- and 3-thienyl, morpholino and p-methoxyphenyl. X is preferably oxygen. The Preferred YR5 moieties are hydroxyl, alkoxysulfinyl of 1 to 7 carbon atoms and furoyloxy.

The compounds of formula I can be obtained by

a) reaction of a compound of formula:

2

wherein R 1, R 2, R 3, R 4 and R 6 have the meaning given above and Hal is halogen,

with a compound of formula

3

wherein X, Y, n, R a, R b and R 5 have the meaning given above and M represents a metal alkaline.

O well

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b) reaction of a compound of formula

4

wherein R 1 -, R 5, R a, R b, X, Y and n have the given meaning previously,

with a compound of formula

5

wherein R 6 -R 8 have the meaning given above, Q is aryl and A - is a anion,

O well

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c) hydrogenation of a compound of formula

6

wherein R 1 -R 8, R a, R b, X, Y and n have the given meaning previously,

or

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d) reaction of a compound of formula

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7

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with a compound of formula

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8

wherein R 1 -R 9, R a, R b, X, Y, Z and n have the given meaning previously,

and if desired, modifying the substituents present in the compound of formula I obtained and / or converting the compound of formula I obtained, in a salt.

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The reaction of a compound of formula II with a compound of formula III is conveniently carried out using the glycol corresponding to compound III, p. ex. in ethylene glycol when n = 2. The alkali metal is preferably sodium. The reaction is conveniently carried out by heating p. ex. to 40-120 ° C. In a preferred version the monosodium salt of ethylene glycol, propylene glycol or butylene glycol is used as the compound of formula III.

The reaction of a compound of formula IV with a compound of formula V can be carried out in the form of yes known, under the usual conditions of a Wittig reaction. The aryl moiety Q is preferably phenyl; anion examples A <-> are Cl <->, Br <->, HSO <-> and tosiloxyl. The compounds that participate in the reaction are reacted conveniently with each other in the presence of a pickup agent acid, p. ex. in the presence of a strong base such as p. ex. he Butullithium, sodium hydride or the sulfoxide sodium salt of dimethyl, or K tert-butylate, but preferably in the presence of an ethylene oxide optionally substituted by lower alkyl, such as 1,2-butylene oxide, possibly in a solvent, e.g. ex. in an ether like diethyl ether or tetrahydrofuran or in an aromatic hydrocarbon such as benzene, in a temperature range between room temperature and the boiling point of the reaction mixture. In the reaction of Wittig, the reactive groups of the reaction participants that they can interfere, such as carboxyl or amino, they are protected conveniently in intermediate reactions p. ex. in the form of a carboxylic acid ester or as the derivative tert.butoxycarbonylamino.

The hydrogenation of a compound of formula VI it can be carried out in a manner known per se for the hydrogenation of olefinic double bonds, e.g. ex. with hydrogen to normal pressure or high pressure in the presence of catalysts noble metal such as Pd, especially Pd on supports such as Pd / C.

In the reaction of a compound of formula XIV with a compound of formula XV, they are conveniently protected in the Last compound, as substituents R 4 -R 9, the groups hydroxyl and amino groups, if present. The groups hydroxyl can be protected p. ex. by silyl groups like the dimethyl t-butylsilyl, or acyl groups such as acetyl; and amino groups can be protected by tert-butoxycarbonyl or benzyloxycarbonyl. These protective groups can be inserted and in the form of themselves already known and after the reaction of compounds XIV and X, be split again.

The substituents present in the compound of Formula I obtained in this way can be modified. For example, A hydroxyl group R 5 can be esterified or etherified. A hydroxyl group R 5 can be converted into an ether group, e.g. ex. tetrahydropyranyl ether or an ester group, e.g. ex. the acetate or on the other hand the groups or quetales contained in the product of reaction first obtained, which p. ex. may be present as substituents and R 5, they can be cleaved as per se already known Methylthio groups can be oxidized to groups Methylsulfinyl or Methylsulfonyl. Radical addition N-heterocyclics such as pyridyl can be oxidized to N-oxides. All these reactions can be carried out according to methods already known. The compounds of formula I can be converted into salts, e.g. ex. alkaline salts as Na and K salts, in the form already known.

The compounds that are used as materials Starting when they are not known or their preparation is not described then they can be prepared analogously to methods already known or to methods described below.

The compounds of formula II can be obtained as detailed in the following scheme:

9

10

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The alkylation of phenol VII with the diethyl chloromalonate results in obtaining compound VIII which is condensed with formamidine acetate or a homologous compound such as acetamidine acetate to form the pyrimidinedione IX derivative. Using phosphorus oxychloride the dichloro compound X which gives compound II is obtained therefrom by reaction with a stoichiometric amount of compound XI. All these reactions are standard operations and can be performed under conditions that are common for these reactions and that are familiar to a person skilled in the specialty.

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The compounds of formula IV can be obtained from according to the following reaction scheme that summarizes continuation:

eleven

The condensation of diethyl allylmalonate with formamidine acetate or a derivative R 4 -substituted and subsequent replacement of the hydroxyl groups per chlorine in the pyrimidinedione obtained, gives as a result the dichloro-pyrimidine XII which condenses with an alkaline salt of R 1, R 2, R 3 -benzenesulfonamide with a transposition of the double bond of the allyl in compound XIII. The reaction of compound XIII with a compound III in the manner already described leads to compound XIV. The oxidative cleavage of the double chain bond side of propenyl in compound XIV finally gives as result aldehyde IV.

Patent DE-OS 1 545 944 gives know about phenyl-sulfonylaminopyrimidines that They have a blood pressure lowering action. These compounds differ from the new sulfonamides according to the invention by the different types of substitution both in the ring of phenyl of the sulfonamide group, as well as in the 2-, 5- position and 6- of the pyrimidine ring. While in the compounds known only one substitution in the position was known for of the phenyl ring, they exist in the compounds according to the invention substituents in ortho and / or goal position and / or para, in the ring of sulfonamide group phenyl. The compounds according to the invention they can be substituted at position 5 of the pyrimidine ring with a vinyl radical, which is not mentioned in the publications anymore above cited.

The inhibitory activity of the compounds of formula I on endothelin receptors can be demonstrated with the test described below:

I. Inhibition of endothelin binding to membranes of the human placenta (see Life Sci 44: 1429 (1989))

The human placenta is homogenized in Tris buffer 5 mM pH 7.4 containing 1 mM MgCl2 and 250 mM sucrose. Be centrifuge the homogenate at 4 ° C and 3,000 g for 15 minutes, and the supernatant containing the plasma membrane fraction is centrifuge with 72,000 g for 30 minutes and the precipitate is washed with 75 mM Tris buffer pH 7.4 containing 25 mM MgCl2. TO then the precipitate obtained in each case from 10 g of the original tissue, it is suspended in 1 ml of 75 mM Tris buffer, pH 7.4, containing 25 mM MgCl2 and 250 mM sucrose, and lyophilizes at -20 ° C in 1 ml aliquots. For the binding test, the lyophilized membrane preparations are thawed and, after centrifuge at 20 ° C and 25,000 g for 10 minutes, resuspend in the assay buffer (50 mM Tris buffer, pH 7.4, containing 25 mM of MnCl2, 1 mM EDTA and 0.5% bovine serum albumin). 100 ml of this membrane suspension containing 70 mg of protein is incubate with 50 ml of125I-endothelin (activity specific 2,200 Ci / mMol) in assay buffer (25,000 cpm, final concentration 20 pM) and 100 ml of assay buffer containing Variable concentrations of the compound under test. The incubation is carried out at 20 ° C for 2 hours or at 4 ° C for 24 hours.

The separation of free radioligands and those that are attached to the membrane, is carried out by filtration to through a fiberglass filter.

The inhibitory activity of the compounds of formula I, determined in this essay is summarized in the table 1 as the IC_ {50}, that is, the concentration [mM] required for inhibit 50% of the specific binding of the 125 I-endothelin.

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TABLE 1

12

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II. Inhibition of contractions induced by endothelin in aortic rings of separate rats

Rings with a length of 5 mm were cut of the thoracic aorta of adult rats Wistar-Kyoto. The endothelium was separated by a slight rub of the surface internal Each ring was immersed at 37 ° C in 10 ml of solution of Krebs-Henseleit in a separate bathroom while gassed with 95% O2 and 5% CO2. The Isometric elongation of the rings. The rings were stretched up to a claim of 3 g. After a 10 minute incubation with the compound or vehicle tested, they are added increasing dosages of endoletin-1. The activity of the compound under test was determined by calculating the dosing ratios, that is, right shift (shift to the highest values) of the EC50 of endothelin induced by 100 mM of the compound under test, the EC 50 the concentration of endothelin required for a contraction half of the maximum. The higher this ratio of Dosage, more potent is the compound tested in inhibit the biological activity of endothelin-1. The EC50 of endothelin in the absence of compounds to be tested is 0.3 nM.

The values thus obtained for the displacement to the right of the EC50 of endothelin with the compounds of formula I, are summarized in table 2.

TABLE 2

13

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III. The inhibitory activity of the compounds of formula I on vasoconstriction can be observed in vivo in rats in the assay described below.

Rats were anesthetized with sodium thiobutabarbital (100 mg / kg i.p.). A catheter was placed to measure the tension systemic arterial blood, through the femoral artery, and a second catheter in the vena cava, via femoral vein, for injection of the compounds tested. A Doppler probe was placed around the left renal artery and connected to a device Doppler measurement. Renal ischemia occurred by pinching the artery left renal at its exit point for 45 minutes. 10 minutes before the induction of ischemia were administered intraarterially (i.a.) the compounds tested, in dosages of 5 mg / kg or intravenously (i.v.) in dosages of 10 mg / kg. In the control tests, the renal perfusion at 43 ± 4% of the preischemic value.

The results obtained with two compounds of Formula I are indicated in Table 3.

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TABLE 3

14

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Based on its ability to inhibit binding with endothelin, the compounds of formula I can be used as medicines for the treatment of diseases associated with vasoconstriction, of increasing occurrences. Examples of such diseases are high blood pressure, coronary heart disease, heart failure, renal ischemia and myocardial, renal failure, dialysis, cerebral ischemia, heart attack, migraine, subarachnoid hemorrhage, syndrome Raynaud and high pulmonary tension. It can also be used in the atherosclerosis, prevention of restenosis after a balloon-induced vascular dilation, inflammations, ulcers gastric and duodenal, ulcus cruris, sepsis gram-negative, shock, glomerulonephritis, colic renal, glaucoma, asthma, in therapy and prophylaxis of complications diabetics and complications in the administration of cyclosporine, as well as in other diseases associated with activities of endothelin

The compounds of formula I can be administered orally, rectally, parentally, p. ex. intravenous, intramuscular, subcutaneous, intrathecal or transdermal or sublingual or as ophthalmic preparations, or in aerosol form. Capsules, tablets, suspensions or solutions for oral administration, suppositories, solutions for injection, eye drops, ointments or sprays, are examples of ways of application.

The preferred form of employment is the application intravenous, intramuscular or oral. The dosages at which compounds of formula I are administered in effective amounts depend on the nature of the specific active ingredient, age and the requirements of the patient and the mode of application. in general dosages of about 0.1 to come into consideration 100 mg / kg body weight per day. The preparations that contain the compounds of formula I may contain inert additives or also pharmacodynamically active. The tablets or granules p. ex. they can contain series of binders, loads, supports or thinners Liquid preparations may be present by example, in the form of a sterile water-miscible solution. Capsules They may contain a filler or thickener in addition to the active ingredient. In addition, additives to improve the taste, as well as substances commonly used as preservatives, stabilizers, moisture retainers and agents emulsifiers as well as salts to vary the osmotic pressure, buffers and other additives.

Support materials and diluents mentioned above may comprise organic substances or inorganic, p. ex. water, gelatin, lactose, starch, stearate magnesium, talcum, gum arabic, polyalkylene glycols, and the like. Is an indispensable requirement that all adjuvants employed in The preparation of the preparations is non-toxic.

The following Examples illustrate the invention more details. Of the abbreviations used, THF means tetrahydrofuran; DMSO means dimethyl sulfoxide; MeOH means methanol; p. ex. means boiling point, and m.p. means melting point.

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Example 1

a) 886 mg of p-t-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, they were added to a solution of sodium glycolate of 3.0 g of ethylene glycol and 138 mg of sodium. The reaction mixture was stirred at 95 ° C under argon for 4 hours. Then it ethylene glycol was distilled off and the residue was partitioned between ethyl acetate and 1N hydrochloric acid. The organic phase is dried and the solvent was distilled off. The crystallized residue with diisopropyl ether. 870 mg of p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide. P.f. 143-148 ° C.

b) 775 mg of sulfonamide above obtained were dissolved in 20 ml of hot ethanol. The solution is treated with a stoichiometric amount of sodium ethylate, to ethanol was then distilled off until it formed a precipitate 3 ml of isopropyl ether was added until Complete the precipitation. 775 mg of p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide sodium, m.p. > 250 ° C.

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The starting material was prepared as follow:

c) 25 g of guaiac and 37 g of chloromalonate of dimethyl were added dropwise successively to a solution of sodium methylate obtained from 150 ml of methanol and 4.6 g of sodium. The suspension was stirred at 45 ° C for 1 hour in the absence of moisture and then methanol was distilled off. He residue was treated with 200 ml of toluene and washed with water, 1% solution of sodium hydroxide and water until the phase Organic was colorless. After drying and evaporating the solvent, The residue was distilled. 39.5 g of dimethyl (o-methoxyphenoxy) malonate. E.g. 128ºC / 7 Pa.

d) 5.5 g of formamidine acetate and 12.7 g of dimethyl (o-methoxyphenoxy) malonate is added, cooling with ice, to a solution of sodium methylate obtained from 150 ml of methanol and 3.5 g of sodium. Mix of reaction was stirred at 0-5 ° C for 1 hour in absence of moisture and then at room temperature for 2 hours. Then the solvent was removed by distillation, and the residue was dissolved in 100 ml of water, the phase Aqueous was extracted with toluene and the organic phases were discarded. The aqueous phase was acidified, whereby the 5- (o-methoxyphenoxy) -6-hydroxy-4 (3H) -pyrimidone.

e) 9.4 g of the pyrimidinone obtained They were previously suspended in 20 ml of acetonitrile and treated with 12 g of collidine. Then, 5 ml were added dropwise of POCl 3 in 15 ml of acetonitrile in the absence of moisture. The reaction mixture was stirred at reflux temperature for 8 hours, then they were distilled off to the solvent and excess reagent The residue was extracted with methylene chloride and washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution. The solution was concentrated and passed through a short column of silica gel with chloride methylene as eluent agent. The eluate was concentrated, the residue was recrystallized with ethanol / hexane. 8.5 g of 4,6-dichloro-5- (o-methoxyphenoxy) pyrimidine, m.p. 79-80 ° C.

f) 0.8 g of 4,6-dichloro-5- (o-methoxyphenoxy) pyrimidine and 1.5 g of p-t-butylsulfonamide potassium in 3 ml of anhydrous dimethyl sulfoxide was heated to 120 ° C under argon for 1.5 hours. Then the dimethyl sulfoxide was distilled off, the residue between ethyl acetate and 1N hydrochloric acid, and the phase Organic washed to neutral pH. The organic phase was dried, The solvent was evaporated and the residue was treated with 3 ml of methanol. Be they got 950 mg of p-t-butyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzene-sulfonamide, m.p. 152 ° C.

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Example 2

Similarly to Example 1, paragraph a), to start from p-isopropyl-N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, the N- [6- (hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-isopropylbenzenesylphonamide, m.p. 142-143 ° C. The compound became analogy to Example 1, paragraph b), with a performance almost quantitative, in water soluble sodium salt.

The starting material was obtained analogously to Example 1, paragraph f), reacting 540 mg of 4,6-dichloro-5- (o-methoxyphenoxy) pyrimidine and 360 mg of p-isopropylbenzene sulfonamide Potassium

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Example 3

Similarly to Example 1, paragraph a), to start from N- [6-Chloro-5- (o-tolyloxy) -4-pyrimidinyl] -p-t-butylsulfonamide the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-tolyloxy) -4-pyrimidinyl] -benzenesulfonamide. P.f. 190-192 ° C.

The starting material was prepared as follow:

Diethyl bromomalonate was converted with sodium o-cresolate in (o-tolyloxy) diethyl malonate, e.g. 120 ° C / 7 Pa, in analogy with Example 1, paragraph c).

In analogy to Example 1, paragraph d), from from the previous malonic ester, the 5- (o-tolyloxy) -6-hydroxy-4 (3H) -pyrimidinone from which it was obtained in analogy to Example 1e), the 4,6-dichloro- (o-tolyloxy) pyrimidine, m.p. 78-79 ° C (ethanol / hexane). The last reaction compound with p-t-butylsulfonamide potassium finally resulted in N- [6-Chloro-5- (o-tolyloxy) -4-pyrimidinyl] -p-t-butylsulfonamide.

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Example 4

In analogy to Example 1, paragraph a), from of the p-t-butyl-N- [2-chloro-5- (o-chlorophenoxy) -4-pyrimidinyl] -benzenesulfonamide, the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-chlorophenyloxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 178-179 ° C (with diisopropyl ether).

The starting material was obtained as follows:

In analogy to Example 1, paragraph e), from of diethyl bromomalonate and o-chlorophenolate of sodium, (o-chlorophenoxy) malonate was obtained of diethyl in the form of a colorless liquid that became analogy to Example 1, paragraph d), in the 5- (o-chlorophenoxy) -6-hydroxy-4- (3H) -pyrimidinone. From the last compound it was obtained by analogy with the Example 1, paragraph e), the 4,6-dichloro-5- (o-chlorophenoxy) pyrimidine, m.p. 76-77 ° C (with ethanol / hexane), and from it by reaction with potassium p-t-butylsulfonamide, se got the p-t-butyl-N- [2-chloro-5- (o-chlorophenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 186-187 ° C (with methanol).

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Example 5

In analogy to Example 1, paragraph a), from of the N- [6-chloro-5- (o-chlorophenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, the N- [6- (2-hydroxyethoxy) -5- (o-chlorophenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 174-175 ° C (with ethyl acetate).

The starting material was prepared in analogy with Example 2, paragraph f), from the 4,6-dichloro-5- (o-chlorophenoxy) pyrimidine and potassium p-isopropylbenzenesulfonamide. E.g. 174-176 ° C (with methanol).

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Example 6

In analogy with Example 1, paragraph a), to start from p-t-butyl-N- [6-chloro-5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 165-167 ° C (with diisopropyl ether).

Potassium salt, m.p. 213-215 ° C it was obtained by reaction of sulfonamide with 0.5N KOH in ethanol.

Sodium salt was prepared in analogy with the Example 1, paragraph b). P.f. 265-270 ° C (with ether diisopropyl).

The starting material was prepared as follow:

Diethyl bromomalonate was converted with m-methoxyphenolate sodium in analogy with the Example 1, paragraph c), in (m-methoxyphenoxy) malonate of diethyl, colorless liquid. E.g. 143 ° C / 0.05 Torr. The ester Malonic thus obtained, became analogy with Example 1, paragraph d), in the 5- (m-methoxyphenoxy) -6-hydroxy-4- (3H) -pyrimidinone from which in analogy with Example 1, paragraph e), prepared the 4,6-dichloro-5- (m-methoxyphenoxy) pyrimidine, m.p. 109-110 ° C. The compound reaction lately cited with the potassium p-t-butylbenzenesulfonamide resulted in the p-t-butyl-N- [6-chloro-5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzene-sulfonamide, m.p. 152 ° C (with methanol).

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Example 7

In analogy to Example 1, paragraph a), from of the p-t-butyl-N- [6-chloro-5-phenoxy-4-pyriminidyl] -benzenesulfonamide the p-t-butyl-N- [6- (2-hydroxyethoxy) -5-phenoxy-4-pyrimidinyl] -benzenesulfonamide, m.p. 165-167 ° C (with diisopropyl ether).

The starting material was prepared as follow:

Diethyl bromomalonate was converted with sodium phenolate in analogy to Example 1, paragraph c), in the diethyl phenoxy-malonate, e.g. 140ºC / 0.05 Torr. TO from the malonic ester was obtained in analogy to Example 1, paragraph e), the 5-phenoxy-6-hydroxy-4 (3H) pyrimidinone and from this it was obtained in analogy to Example 1, paragraph e), 4,6-dichloro-5-phenoxypyrimidine, m.p. 89-90 ° C (with ethanol / hexane). The reaction of compound last cited, with p-t-butyl benzenesulfonamide potassium resulted in obtaining the p-t-butyl-N- [6-chloro-5-phenoxy-4-pyrimidinyl] -benzenesulfonamide, m.p. 143-144 ° C.

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Example 8

In analogy to Example 1, paragraph a), from of the 4,6, -dichloro-5- (p-methoxyphenoxy) -4-pyrimidine, the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 141-142 ° C.

The starting material was prepared in analogy to Example 1, paragraphs c), d) and e), by reaction of the bromomalonate of diethyl with sodium p-methoxyphenolate obtaining the (p-methoxyphenoxy) malonate of diethyl e.g. 140 ° C / 7 Pa, and in a subsequent reaction the 5- (p-methoxyphenoxy) -6-hydroxy-4 (3H) pyrimidinone and, respectively, the 4,6-dichloro-5- (p-methoxyphenoxy) -4-pyrimidine, m.p. 107-108 ° C (with ethanol / hexane).

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Example 9

In analogy to Example 1, paragraph a), from of the p-t-butyl-N- [6-chloro-5- (o-ethoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-ethoxyphenoxy) 4-pyrimidinyl] -benzenesulfonamide, m.p. 120-121 ° C (with diisopropyl ether).

The starting material was prepared from ethyl chloromalonate in analogy to Example 1, paragraphs c), d), e) and f), via the following intermediate compounds:

(o-ethoxyphenoxy) malonate dimethyl, e.g. 150ºC / 7 Pa,

5- (o-ethoxyphenoxy) -6-hydroxy-4 (3H) pyrimidinone,

4,6-dichloro-5- (o-ethoxyphenoxy) -4-pyrimidine,

5-p-t-butyl-N- [6-chloro-5- (o-ethoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 162-163 C (with methanol).

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Example 10

In analogy to Example 1, paragraph a) from of the p- (2,2-dimethylpropyl) -N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, the p- (2,2-dimethylpropyl) -N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 136-137 ° C (with diisopropyl ether).

The starting material was prepared in analogy to Example 1, paragraphs c), d) and f), via the following compounds intermediate:

Chloride p- (2,2-dimethylpropyl) benzenesulfonyl, e.g. 105 ° C / 0.005 Torr.,

2,2-dimethyl-p- (2,2-dimethylpropyl) benzenesulfonamide potassium,

p- (2,2-dimethylpropyl) -N- [6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 164-165 ° C (with methanol).

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Example 11

In analogy to Example 1, paragraph a), from of the N- [6-Chloro-2-methyl-5- (m-methoxyphenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 152-153 ° C, the p-isopropyl-N- [6-hydroxyethoxy) -2-methyl-5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, m.p. 129-130 ° C (with diisopropyl ether).

The starting material was prepared as follow:

In analogy to Example 1, paragraph e), using acetamidine hydrochloride instead of acetate formamidine, the (m-methoxyphenoxy) malonate of dimethyl became 5- (m-methoxyphenoxy) -2-methyl-6-hydroxy-4 (3H) pyrimidinone. From it, it was prepared in analogy to Example 1, paragraph the A 4,6-dichloro-2-methyl-5- (m-methoxyphenoxy) pyrimidine and from the latter with potassium p-isopropylbenzenesulfonamide was prepared N- [6-Chloro-2-methyl-5- (m-methoxyphenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 152-153 ° C (with methanol).

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Example 12

In analogy to Example 1, paragraph a), from of the N- [6-Chloro-5- (o-methoxy) -2-phenyl-4-pyrimidinyl] -p-isopropyl-benzenesulfonamide the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-phenyl-4-pyrimidinyl] p-isopropylbenzenesulfonamide.

The starting material was prepared in analogy to Example 1, paragraphs d), e) and f), from (o-methoxyphenoxy) dimethyl malonate via 5- (o-methoxy) 2-phenyl-6-hydroxy-4 (3H) -pyrimidinone, 4,6-dichloro-2-phenyl-5- (o-methoxyphenoxy) pyrimidine, m.p. 135-136 ° C, and N- [6-Chloro-5- (o-methoxy) 2-phenyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 190-191 ° C (with methanol).

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Example 13

1.3 ml of 1.6 M butyllithium in hexane is added at -20 ° C to 780 mg of benzyltriphenylphosphine chloride in 10 ml of absolute tetrahydrofuran. The reaction mixture was stirred. at -20 ° C for 15 minutes and then treated with 280 mg acetate 2 - [(5-formyl-6-p-toluenesulfonamido-4-pyrimidinyl) oxy] ethyl. The reaction mixture was allowed to warm to room temperature and It was stirred at room temperature for 2 hours. The tetrahydrofuran by distillation under reduced pressure, the residue in ethyl acetate and the organic phase was washed with water and Saturated sodium chloride solution, dried and evaporated. The residue chromatographed on silica gel with methylene chloride / acetate of ethyl (9: 1 and 8: 2). 160 mg of acetate were obtained 2 [[5 - [(E / Z) -styryl] -6-p-toluenesulfonamido-4-pyrimidinyl] oxy] ethyl, m.p. 146-156 ° C.

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The starting material was prepared as follow:

From 5-allyl-4,6-dichloropyrimidine-p-toluenesulfonamide potassium separated the N- [6-chloro-5 - [(E / Z) propenyl] -4-pyrimidinyl] -p-toluenesulfonamide and from it by reaction with sodium ethylene glycol, it prepared the N- [6- (2-hydroxyethoxy) -5 - [(E / Z) -propenyl] -4-pyrimidinyl] -p-toluenesulfonamide, m.p. 130-132 ° C. The reaction with acetic anhydride in presence of pyridine in tetrahydrofuran resulted in acetate 2 - [[5- (E / Z) -propenyl] -6-p-toluenesulfonamido-4-pyrimidinyl] oxy] ethyl, m.p. 160-163 ° C.

390 mg of the aforementioned compound and 8 mg of osmium tetroxide were added to a mixture of 2.5 ml of water and 7 ml of dioxane and then 450 mg of m-sodium periodate at room temperature for 30 minutes and after stirring at room temperature for 2 hours another 8 mg of osmium tetroxide was added. The mixture of reaction was stirred for a further 5 hours and elaborated, whereby got the acetate of 2 - [(5-formyl-6-p-toluenesulfonamido-4-pyrimidinyl) oxy] ethyl, m.p. 130-144 ° C (after crystallizing with acetate of ethyl and diethyl ether).

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Example 14

120 mg acetate 2 - [[5 - [(E / Z) -styryl] -6-p-toluene-sulfonamido-4-pyrimidinyl] oxy] ethyl, were hydrogenated in 3 ml of absolute ethanol and 3 ml of absolute tetrahydrofuran in the presence of 4 mg of palladium / carbon at 5%. Once the hydrogen uptake was complete, the catalyst by filtration and the organic phases evaporated to reduced pressure The residue was chromatographed on silica gel. with ethyl acetate obtaining 110 mg of acetate 2 - [[5-phenethyl-6-p-toluenesulfonamido-4-pyrimidinyl] oxy] ethyl, m.p. 120-123º C.

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Example 15

80 mg acetate 2- (5-phenethyl-6-p-toluenesulfonamido-4-pyrimidinyl) oxy] ethyl in 5 ml of methanol they were stirred with 53 mg of potassium carbonate finely pulverized at 20 ° C for 15 hours. Then the methanol was removed under reduced pressure, the residue was extracted with ethyl acetate, the organic phase was washed with water and solution saturated with sodium chloride, dried and evaporated. The residue is chromatographed on silica gel with methylene chloride / acetate ethyl (1: 1) and ethyl acetate. 40 mg of N- [6- (2-hydroxyethoxy) -5-phenethyl-4-pyrimidinyl] -p-toluenesulfonamide, in the form of a white resin.

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Example 16

In analogy to Example 15, from acetate from 2 - [[5 - [(E / Z) -styryl] -6-toluenesulfonamido] -4-pyrimidinyl] oxy] ethyl, the N- [6- (2-hydroxyethoxy) -5 - [(E / Z) -styryl-4-pyrimidinyl-p-toluenesulfonamide in the form of a white resin.

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Example 17

In analogy to Example 1, paragraph a), from of the N- [6-Chloro-5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl-p-isopropylbenzenesulfonamide and sodium ethylene glycol was obtained the N- [6- (2-hydroxyethoxy) -5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 182-183 ° C (with methylene chloride and ether isopropyl).

The starting material was prepared from 4,6-dichloro-5- (2,4,6-trichlorophenoxy) pyrimidine and p-isopropylbenzenesulfonamide, m.p. 217-218 ° C (with methylene chloride and ether isopropyl).

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Example 18

In analogy to Example 1, paragraph a), from of the N- [6-Chloro-5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -o-toluenesulfonamide and sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -6- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -o-toluenesulfonamide, m.p. 144-145 ° C (with isopropyl ether).

The starting material was prepared from the 4,6-dichloro-5- (2,4,6-trichlorophenoxy) -pyrimidine and o-toluenesulfonamide, m.p. 107-109 ° C (with isopropyl ether).

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Example 19

In analogy to Example 1, paragraph a), from of the N- [6-Chloro-5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -2,4-xylenesulfonamide and sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -2,4-xylenesulfonamide, m.p. 157-158 ° C (with isopropyl ether).

The starting material was prepared as follow:

16.9 g of anhydrous K 2 CO 3 were added to a solution of 18.0 of 2,4-6-trichlorophenol and 32.0 g of diethyl bromomalonate in 180 ml of acetone and 20 ml of toluene. The reaction mixture was heated to reflux, stirring, for 24 hours, The solution was separated from the precipitate by filtration and evaporated to reduced pressure The residue was extracted with toluene, the organic solution with a 5% sodium carbonate solution at then with water, dried with sodium sulfate and after filtered off the salt by aspiration, evaporated to reduced pressure The residue was distilled at a pressure of ≤ 1 mm Hg, which resulted in a colorless oil (p-e-171-174 ° C) at from which with formamidine acetate and sodium methylate it got the 5- (2,4,6-trichlorophenoxy) -4.6 (3H, 5H) -pyrimidinedione, m.p. > 270 ° C, which prior to the next reaction is dried at 80 ° C overnight under reduced pressure.

A solution of 7.6 of 5- (2,4,6-trichlorophenoxy) -4,6- (3H, 5H) -pyrimidinone, 6.6 g of tetraethylammonium chloride, 3.3 ml of collidine, 13.7 ml of POCl 3 in 70 ml of CH 3 CN, heated at reflux for 4.5 hours, the solution was evaporated under reduced pressure, the residue was treated three times with ether, the combined organic solutions were filtered overnight, evaporated under reduced pressure and the residue was recrystallized with ether and n-hexane. Be got the 4,6-dichloro-5- (2,4,6-trichlorophenoxy) pyrimidine, m.p. 104-105 ° C.

From the 4,6-dichloro-5- (2,4,6-trichlorophenoxy) pyrimidine and 2,4-xylenesulfonamide the N- [6-Chloro-5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -2,4-xylenesulfonamide, m.p. 267 ° C (with acetonitrile and isopropyl ether).

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Example 20

By reaction of the 4,6-dichloro-5 - [(2-methoxy-4-methyl) phenoxy] pyrimidine with the p-t-butylbenzenesulfonamide and a then with sodium ethylene glycol the p-t-butyl-N- [6- (2-hydroxyethoxy) -5 - [(2-methoxy-p-tolyl) oxy] -4-pyrimidinyl] -benzenesulfonamide in the form of a solid.

The starting material was prepared by reaction of methylguayacol with diethyl bromomalonate and then with formamidine acetate to give the 5 - [(2-Methoxy-4-methyl) phenoxy] -4.6 (3H, 4H) -pyrimidinedione, m.p. 234-236 ° C and subsequent reaction of the last composed with POCl3.

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Example 21

By reaction of the 4,6-dichloro-5 - [(2-methoxy-4-methyl) phenoxy] pyrimidine with p-isopropylbenzenesulfonamide and a then with sodium ethylene glycol, the N- [5- (2-Methoxy-4-methyl) phenoxy] pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 135-136 ° C (with ethyl acetate).

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Example 22

By reaction of the 4,6-dichloro-5 - [(2-methoxy-4-methyl) phenoxy] pyrimidine with the o-ethylbenzenesulfonamide and then with sodium ethylene glycol, the N- [5- (2-Methoxy-4-methyl) phenoxy-6- (2-hydroxyethoxy) -4-pyrimidinyl] -o-ethylbenzenesulfonamide in the form of a solid.

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Example 23

By reaction of the 4,6-dichloro-5- (2-methoxy) phenoxy-2-methylpyrimidine with the p-tert.butylphenylsulfonamide and then with sodium ethylene glycol the p-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, m.p. 123-124 ° C (with ethyl acetate).

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Example 24

By reaction of the 4,6-dichloro-5- (2-methoxy) phenoxy-2-methylpyrimidine with p-isopropylbenzenesulfonamide and a then with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 124-126 ° C (with acetonitrile, isopropanol and Water).

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Example 25

By reaction of the 4,6-dichloro-5- (2-methoxyphenoxy-2-trifluoromethylpyrimidine with p-isopropylbenzenesulfonamide and a then with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-trifluoromethyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide in the form of a solid.

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Example 26

By reaction of the 4,6-dichloro-5- (2-methoxyphenoxy-2-trifluoromethylpyrimidine with p-tert.butylbenzenesulfonamide and with ethylene glycol sodium was obtained the p-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2- (trifluoromethyl) -4-pyrimidinyl] -benzenesulfonamide, m.p. 190-192 ° C (with toluene). Sodium salt: P.f. 288-289 ° C.

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Example 27

By reaction of 5- (1,3-benzodioxol-5-yloxy) -4,6-dichloropyrimidine with p-tert.butylphenylsulfonamide and then with sodium ethylene glycol, N- [5- (1,3-benzodioxol-) was obtained 5-yloxy) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p-tert.
butylbenzenesulfonamide in the form of a solid.

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Example 28

By reaction of the 5- (1,3-benzodioxol-5-yloxy) -4,6-dichloropyrimidine with p-isopropylbenzenesulfonamide and a then with sodium ethylene glycol the N- [5- (1,3-benzodioxol-5-yloxy) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p-isopropyl-benzenesulfonamide in the form of a solid.

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Example 29

By reaction of the 5- (2-Methoxyphenoxy-4,6-dichloropyrimidine with the o-methoxyphenylsulfonamide and then with ethylene glycol sodium was obtained the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -o-methoxybenzenesulfonamide, m.p. 164-165 ° C (with ethyl acetate).

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Example 30

By reaction of the p-tert.butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide With the monosodium salt of 1,4-butanediol, it was obtained the p-tert.butyl-N- [6- (4-hydroxybutyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide in the form of a white foam.

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Example 31

By reaction of the 4,6-dichloro-5- (2-naphthyloxy) pyrimidine with the p-isopropylphenylsulfonamide and then with the ethylene glycol sodium salt the N- [6- (2-hydroxyethoxy) -5- (2-naphthyloxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, m.p. 160-161 ° C (with isopropyl ether).

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Example 32

By reaction of the 4,6-dichloro-5- (2-naphthyloxy) pyrimidine with the p-tert.butylphenylsulfonamide and then with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (2-naphthyloxy) -4-pyrimidinyl] -p-tert-butylbenzenesulfonamide, m.p. 197-198 ° C (with isopropyl ether).

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Example 33

By reaction of the 4,6-dichloro-5- (o-methoxyphenoxy) -2-propylpyrimidine with the p-isopropylphenylsulfonamide and then with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-propyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, in the form of a solid.

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Example 34

By reaction of the 4,6-dichloro-5- (o-methoxyphenoxy) -2-propylpyrimidine with the p-tert.butylphenylsulfonamide and then with sodium ethylene glycol the p-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-propyl-4-pyrimidinyl] -benzenesulfonamide.

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Example 35

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with α, α, α-trifluor-p-toluenesulfonamide and then with sodium ethylene glycol the α, α, α-trifluor-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-toluenesulfonamide, m.p. 144-145 ° C (with ethyl acetate).

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Example 36

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with the p-chlorophenylsulfonamide and then with ethylene glycol sodium was obtained the p-chloro-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, m.p. 134-135 ° C (with ethyl acetate).

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Example 37

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with the p- (trifluoromethoxy) benzenesulfonamide and then with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p- (trifluoromethoxy) benzenesulfonamide, m.p. 138-140 ° C (with ethyl acetate).

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Example 38

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with the o-ethylbenzenesulfonamide and then with ethylene glycol sodium was obtained the o-ethyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, in the form of a white foam.

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Example 39

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with p-toluenesulfonamide and with sodium ethylene glycol the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-toluenesulfonamide, in the form of a white foam.

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Example 40

By reaction of the 4,6-dichloro-5- (o-methoxy) phenoxy-2-methylpyrimidine with 2-naphthylsulfonamide and then with ethylene glycol sodium was obtained the N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-naphthylsulfonamide, in the form of a foam.

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Example 41

By reaction of the p-tert.butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide with the monosodium salt of 1,3-propanediol, it was obtained the p-tert.butyl-N- [6- (3-hydroxypropoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, in the form of a white foam.

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Example 42

In analogy to Example 1, paragraph a), 300 mg from p-t-butyl-N- [6-chloro-5 - [(o-methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide they became N- [6- (2-hydroxyethoxy) -5 - [(o-methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide. 250 mg of p-t-butyl-N- [6- (2-hydroxyethoxy) -5 - [(o-methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide, m.p. 149-150 ° C.

The starting material was prepared from the following form:

to the dimethyl (o-methylthio) phenoximalonate is obtained from dimethyl chloromalonate and the (omethylthio) phenol in analogy to Example 1, paragraph c). TO give birth of 17 g of (o-methylthio) phenol se they obtained 23 g of malonate, with toluene-hexane.

b) 9.15 g of 5 - [(o-methylthio) phenoxy] -6-hydroxy-4- (3H) -pyrimidinone, MS: 250 (M), were obtained from 13.5 g of the malonate from of a) and formamidine acetate in analogy to Example 1, paragraph d).

c) 2.5 g of this compound and 2.9 g of diisopropylethyl amine were suspended in 15 ml of acetonitrile 2 ml of POCl3 was added dropwise to the suspension and then the sample was boiled under reflux for 5 hours. The 4,6-dichloro-5 - [(o-methylthio) phenoxy] pyrimidine after elaborating analogously to Example 1, paragraph e). After of crystallization with n-hexane, 1 g of pyrimidine derivative, m.p. 89-90 ° C.

d) In analogy to Example 1, paragraph f), 580 mg of 4,6-dichloro-5 - [(o-methylthio) phenoxy] pyrimidine converted with 850 mg potassium p-t-butylbenzenesulfonamide in p-t-butyl-N- [6-chloro-5 - [(o-methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide. After crystallizing with MeOH, 480 mg of crystals were obtained. whites, m.p. 154-155 ° C.

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Example 43

a) In analogy to Example 1, paragraph a), 350 mg of p-t-butyl-N - [(6-chloro-5- (o-methoxyphenoxy) -2-phenyl-4-pyrimidinyl] -benzenesulfonamide they became p-t-butyl-N- [6- (2-hydroxyethoxy) -2-phenyl-4-pyrimidinyl] -benzenesulfonamide. After crystallization with diisopropyl ether, 330 mg was obtained. of white crystals, m.p. 160-161 ° C.

b) 225 mg of this compound dissolved in EtOH The stoichiometric amount of KOH was added to the solution in MeOH The solvent was then distilled off and added isopropyl ether to the residue whereby the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-phenyl-4-pyrimidinyl] -benzenesulfonamide potassium, MS: 588 [(M + K) +].

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Example 44

In analogy to Example 1, paragraph a), from N- [2-amino-6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-tert.
butylbenzenesulfonamide was obtained N- [2-amino-6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-tert.butyl-benzene-sulfonamide, white crystals of melting point 168 ° C ( with diisopropyl ether).

The starting material was prepared from the following form:

a) 7.65 g of (5-o-methoxy) phenoximalonate of dimethyl and 3 g of guanidine hydrochloride were added to a solution of 2.3 g of Na in 100 ml of methanol. The suspension was stirred at room temperature under argon for 3 hours. TO then the methanol was distilled off and the residue was absorbed in water. After the usual treatment as it has been described above, the compound was precipitated by addition dropwise acetic acid until the pH of the solution reached the value 4,5. 6.4 g of crude product were obtained of which 1.35 g were suspended in 10 ml of dioxane. They were added to it successively 1.4 g of N-ethyldiisopropylamine, 2 ml of POCl3 and 1 g of triethylbenzylammonium chloride. The mixture under reflux under argon while stirring vigorously. After 30 minutes the solvent was removed from the distillation mixture, the residue was absorbed in ethyl acetate and It was extracted with H2O and saturated NaHCO3 solution. The purification was performed by silica gel chromatography (CH 2 Cl 2 -ethyl acetate, 9: 1 by volume, as eluent). The 2-amino-4,6-dichloro-5- (o-methoxyphenoxy) pyrimidine as a colorless solid. P.f. 190 ° C.

b) 0.5 g of the above dichloro compound and 0.75 g of sodium p-tert.butylbenzenesulfonamide in 2 ml of DMSO were converted at 90 ° C in N- [2-amino-6-chloro-5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-tert-butylbenzenesulfonamide, m.p. 194-195 ° C.

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Example 45

a) In analogy to Example 1, paragraph a), 478 mg of p-tert.butyl-N- [6-chloro-2-methyl-5- [o- (methylthio) phenoxy] pyrimidinyl] -benzenesulfonamide and Na glycolate in ethylene glycol became the p-tert.butyl-N- [6- (2-hydroxyethoxy) -2-methyl-5- [o-methylthio) -phenoxy] -4-pyrimidinyl] -benzenesulfonamide, m.p. 166-167 ° C.

b) 225 mg of this compound became the sulfonamide salt by adding the stoichiometric amount of aqueous NaOH. It was then diluted with methanol to give a homogeneous solution. 100 mg of NaIO4 dissolved in 2 ml of H2O was added to this solution and the mixture was stirred at room temperature for 8 hours. Then evaporated until dry. The residue was partitioned between ethyl acetate and Aqueous H2SO4 0.1N. After evaporating the organic phase, the crystallized p-tert.butyl-N- [6- (2-hydroxyethoxy) -2-methyl-5- [o- (R, S-methylsulfinyl) phenoxy] -4-pyrimidinyl] -benzenesulfonamide with diisopropyl ether. 150 mg of white crystals were obtained. MS: m / e = 520 (M + H) +.

The starting material was prepared as follow:

5.4 g of (o-methylthiophenoxy) dimethyl malonate and 2.1 g of acetamidine hydrochloride became 6-hydroxy-2-methyl-5- [o- (methylthio) phenoxy] -4 (3H) -pyrimidine and it became 4,6-dichloro-2-methyl-5- [o- (methylthiophenoxy) -pyrimidine, m.p. 132-133 ° C.

0.9 g of the above dichloro compound and 1.3 g of p-tert-butyl benzenesulfonamide potassium became p-tert.butyl-N- [6-chloro-2-methyl-5- [o-methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide. P.f. 162-163 ° C.

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Example 46

1.22 g of (S) -1,2-di-O-isopropylidenglycerol they were added dropwise under argon to a suspension of 170 mg of NaH in 2 ml of anhydrous THF. Then they were added 1.03 g of p-tert.butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (p-methoxy-phenyl) -4-pyrimidinyl] -benzenesulfonamide and 2 ml of DMSO. The mixture was allowed to react at 95 ° C for 4 hours. by distilling the THF. Then 0.5 ml of H2O and the mixture of solvent and excess reagent are distilled off under reduced pressure. The residue was extracted with 20 ml of dioxane; 1 ml of 1N aqueous HCl was added and the mixture was allowed to react at 65 ° C for 45 minutes. Then evaporated Mix until dry. The residue was partitioned between acetate ethyl and 1N hydrochloric acid. After the usual preparation of compound, this was purified on silica gel with ethyl acetate as eluent. 0.98 g of (S) -4-tert.butyl-N- [6- (2,3-dihydroxypropyl-oxy) -5- (o-methoxyphenoxy) -2- (p-methoxyphenyl) -pyrimidin-4-yl] -benzenesulfonamide,  m.p. 141-142 ° C (with diethyl ether).

The starting material was prepared as follow:

In analogy to Example 1, paragraph d), 7.63 g of dimethyl (o-methoxyphenoxy) malonate and 5.6 g of hydrochloride p-methoxy-benzamidine condensed to give 2- (p-methoxy-phenyl) -5- (o-methoxyphenoxy) -6-hydroxy-4 (3H) -pyrimidinone. The reaction of this compound in analogy to Example 1, paragraph e), resulted in 4,6-dichloro-2- (p-methoxyphenyl) -5- (o-methoxyphenoxy) -pyrimidine, m.p. 113-114 ° C, from which, in analogy to Example 1 paragraph f), the p-tert.butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2- (p-methoxyphenyl) -4-pyrimidinyl] -benzenesulfonamide, m.p. 221-222 ° C.

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Example 47

210 mg of 4-tert-butyl-N- [5- (2-chloro-5-methoxyphenoxy) -2-ethyl-6- (2-methylsulfanyl-ethoxy) -pyrimidin-4-yl] -benzene-sulfonamide they were dissolved in 5 ml of MeOH and 0.2 ml of NaOH. 95 mg was added of NaIO4 dissolved in 0.5 ml of H2O thereto and the mixture it was stirred at room temperature for 5 hours, which formed a suspension Then 0.2 ml of 1N HCl was added mixture was evaporated to dryness. The residue was distributed between ethyl acetate and 0.1N HCl and was prepared as usual. For your purification the compound was chromatographed on silica gel using ethyl acetate - MeOH (6: 1 by volume) as eluent. Be they got 160 mg of (RS) -4-tert.butyl-N- [5- (2-chloro-5-methoxyphenoxy) -2-ethyl-6- (2-methylsulfinyl-ethoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a white powder. MS: 581 (M).

The starting material was prepared as follow:

In analogy to Example 1, paragraph c), from of the 2-chloro-5-methoxy-phenol and dimethyl chloromalonate the (2-Chloro-5-methoxyphenoxy) malonate dimethyl, m.p. 68-69 ° C. Condensation with Propanidine hydrochloride resulted in 2-ethyl-5- (2-chloro-5-methoxyphenoxy) -6-hydroxy-4 (3H) -pyrimidinone from which in analogy to Example 1, paragraph e), the 4,6-dichloro-2-ethyl-5- (2-chloro-5-methoxyphenoxy) -pyrimidine, m.p. 113-113.5 ° C. this compound became analogously to Example 1, paragraph f), in the 4-tert-butyl-N- [6-chloro-5- (2-chloro-5-methoxyphenoxy) -2-ethyl-pyrimidin-4-yl] -benzenesulfonamide, m.p. 142-143 ° C (with ethanol).

300 mg of 2- (methylthio) ethanol, under argon to a suspension of 63 mg of NaH in anhydrous THF. Then they were added to it 300 mg of the sulfonamide obtained above and 1 ml of 1,3-dimethyl-3,4,5,6-tetrahydro-2 (1H) -pyrimidinone. The mixture was allowed to react at 80 ° C for 3 hours. After the normal preparation of the reaction mixture and gel purification of silica (CH2Cl2-diethyl ether, 95/5 by volume, as eluent), 160 mg of 4-tert-butyl-N. [5- (2-Chloro-5-methoxyphenoxy) -2-ethyl-6- (2-methylsulfanyl-ethoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a white powder.

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Example 48

a) In analogy to Example 1, from the 4-tert-butyl-N- [6-chloro-5- (2-chloro-5-methoxyphenoxy) -2-methylpyrimidin-4-yl] -benzenesulfonamide the 4-tert-butyl-N- [5- (2-chloro-5-methoxyphenoxy) -6- (2-hydroxyethoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide. From 500 mg of the starting material 430 mg of white crystals ,. P.f. 141-141.5 ° C (with ether isopropyl).

b) 140 mg of the compound obtained is esterified with 3-furancarboxylic acid in the following conditions: 140 mg of the sulfonamide obtained above, 170 mg of hydrochloride N-ethyl-N '- (3-dimethylaminopropyl) -carbodiimide, 170 mg of Et3N and 5 mg of dimethylamino pyridine were dissolved in 2 ml of dichloromethane and the solution was allowed to stand at room temperature for 24 hours. Then 5 ml of THF and 1 ml of H2O was added thereto, and the solution was stirred for 30 minutes It was then evaporated to dryness. He residue was partitioned between dichloromethane and 1N HCl, then washed three times with H2O and isolated as usual. He compound was purified on silica gel using dichloromethane-diethyl ether (95: 5 by volume) as eluent. Be they got 120 mg of 4-tert-butyl-N- [5- (2-chloro-5- (2-chloro-5-methoxyphenoxy) -6- (2- (3-furoyloxy) ethoxy) -2-methyl-pyrimidin-4-yl ] -benzenesulfonamide.

The starting material was prepared as follow:

In analogy to Example 1, paragraph d), condensed the (2-Chloro-5-methoxyphenoxy) malonate dimethyl with acetamidine hydrochloride to give (2-Chloro-5-methoxyphenoxy) -2-methyl-6-hydroxy-4 (3H) -pyrimidinone. From it, in analogy to Example 1, paragraph e), got the 4,6-dichloro-5- (2-chloro-5-methoxyphenoxy) -2-methyl-pyrimidine, m.p. 125-130 ° C, and from it in analogy to example 1, paragraph f), the 4-tert-butyl-N- [6-chloro-5- (2-chloro-5-methoxyphenoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide, m.p. 182 ° C (with MeOH).

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Example 49

In analogy to Example 47, 90 mg of N- [5- (2-Chloro-5-methoxyphenoxy) -6- (2-methylsulfanyl-ethoxy) -pyrimidin-4-yl] -1,3-benzodioxol-5-sulfonamide oxidized with NaIO4 to give (RS) -N- [5- (2-Chloro-5-methoxyphenoxy) -6- (2-methyl-sulfinyl-ethoxy) -pyrimidin-4-yl] -1,3-benzodioxol-5-sulfonamide. 65 mg of a powder were obtained. MS: 542.1 (M + H +).

The starting material was prepared as follow:

In analogy to Example 1, paragraph d), condensed the (2-Chloro-5-methoxyphenoxy) malonate dimethyl with formamidine acetate to give the (2-Chloro-5-methoxyphenoxy-6-hydroxy-4 (3H) -pyrimidinone. From it in analogy to Example 1, paragraph e), it is got the 4,6-dichloro-5- (2-chloro-2-methoxyphenoxy) -pyrimidine, m.p. 88-89 ° C (with ethanol).

The 611 mg reaction of the 4,6-dichloro-5- (2-chloro-2-methoxyphenoxy) -pyrimidine with 813 mg of 1,3-benzodioxol-5-sulfonamide Potassium resulted in obtaining 525 mg of N- [6-Chloro-5- (2-chloro-5-methoxyphenoxy) -pyrimidin-4-yl] -1,3-benzodioxol-5-sulfonamide. The compound cited last became N- [5- (2-Chloro-5-methoxyphenoxy) -6- (2-methyl-sulfanylethoxy) -pyrimidin-4-yl] -1,3-benzodioxol-5-sulfonamide, as described in the preparation of the starting material in the Example 47

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Example 50

A solution of 0.11 g of sodium in 3.0 ml of ethylene glycol was heated at 110 ° C with 0.265 g of 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophene) -2-yl-pyrimidin-4-yl] -benzene-sulfonamide, cooled for another 4 hours, poured on ice and adjusted to pH 3 with 1 M tartaric acid. The suspension obtained was extracted with ethyl acetate, the organic extracts were combined, washed with water, dried over sodium sulfate and concentrated to reduced pressure The residue was chromatographed on silica gel. with CH 2 Cl 2 -ethyl acetate 9: 1, getting the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] -benzenesulfonamide in the form of a white foam. MS: M + = 555.

The starting material was prepared as follow:

a) A solution of 5.17 Na in 200 ml of Absolute methanol was treated with 21.15 g of diethyl o (methoxyphenoxy) malonate and 16.2 g of hydrochloride thiophene-2-carboxamidine and the suspension was stirred at room temperature overnight and was evaporated under reduced pressure. The residue was absorbed in 1N NaOH, the alkaline solution was acidified with 1N HCl, the precipitate separated by filtration with aspiration, washed thoroughly with water and dried vacuum at 80 ° C. The 5- (o-methoxyphenoxy) -2- (2-thienyl) -4,6-dihydroxy-pyrimidine from p.f. > 250 ° C (decomposition) was used in the new step without subsequent purification.

b) A suspension of 4.6 g of 5- (o-methoxyphenoxy) -2- (2-thienyl) -4,6-dihydroxy-pyrimidine, 4.7 ml of N, N-diisopropyl-N-ethylamine and 6.4 g of PCl5, boiled under reflux for 20 hours. TO the mixture was then evaporated under reduced pressure, the residue was poured on ice and extracted with ethyl acetate. Extracts together they were washed with water, dried and evaporated in vacuo. He residue was chromatographed on silica gel with toluene getting the 4,6-dichloro-5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidine, m.p. 118-120 ° C.

c) A solution of 0.353 g of 4,6-Dichloro-5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidine in 5 ml of DMSO it was heated to 150 ° C with 0.376 g of p-tert.butylbenzenesulfonamide for 30 minutes. The solution was concentrated under high vacuum and the oily residue was poured on ice, acidified (pH = 3) and the suspension was extracted with ethyl acetate. The organic extracts were combined, washed with water, dried with sodium sulfate and concentrated under reduced pressure. The residue was chromatographed on silica gel. with toluene-ethyl acetate 9: 1 obtaining the 4-tert-butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] -benzene-sulfonamide, in the form of a white foam.

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Example 51

In an analogous way to Example 50 from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-3-yl) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (thiophene-3-yl] -pyrimidin-4-yl] -benzenesulfonamide, m.p. 152-153 ° C (with toluene).

The 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-3-yl) -pyrimidin-4-yl] -benzenesulfonamide (foam) was prepared starting from the hydrochloride of thiophene-3-carboxamidine pathway rac-5- (2-methoxyphenoxy) -2- (thiophene-3-yl) -3,4,5,6-tetrahydropyrimidin-4,6-dione (solid of m.p.> 250 ° C) and the 4,6-dichloro-5- (2-methoxyphenoxy) -2- (thiophen-3-yl) -pyrimidine (mp 98-99 ° C).

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Example 52

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2- (furan-2-yl) -5- (2-methoxyphenoxy) pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [2- (furan-2-yl) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid amorphous.

The 4-tert.butyl-N- [6-chloro-2- (furan-2-yl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide (foam) was prepared starting from the hydrochloride of furan-2-carboxamidine pathway rac-2- (furan-2-yl) -5- (2-methoxyphenoxy) -pyrimidin-4,6-dione (solid with a decomposition point of 255-258 ° C) and the 4,6-dichloro-2- (furan-2-yl) -5- (2-methoxyphenoxy) -pyrimidine.

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Example 53

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2-furan-3-yl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [2- (furan-3-yl) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid of m.p. 120-122 ° C (with toluene / n-hexane).

The 4-tert-butyl-N- [6-chloro-2- (furan-3-yl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide (foam) was prepared starting from the hydrochloride of furan-3-carboxamidine pathway rac-2- (furan-3-yl) -5- (2-methoxyphenoxy) -4,6-dioxo-1,4,5,6-tetrahydropyrimidine (solid with m.p. greater than 300 ° C with decomposition) and the 4,6-dichloro-2- (furan-3-yl) -5- (2-methoxyphenoxy) -pyrimidine.

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Example 54

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2-pyridin-2-yl] -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid with a m.p. above 250 ° C (with acetate of ethyl).

4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide (mp 197-
198 ° C with isopropyl ether) was prepared starting from pyridin-2-carboxamidine hydrochloride via 5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) pyrimidin-4,6-diol and 4,6-dichloro-5- (2-Methoxyphenoxy) -2- (pyrimidin-2-yl] -pyrimidine, mp 122-123 ° C.

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Example 55

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid of m.p. 166-167 ° C with acetone ether.

The 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidin-4-yl] -benzenesulfonamide potassium (1: 1), m.p. 193-196 ° C with H2O, se prepared starting from the hydrochloride of pyridin-4-carboxamidine pathway 5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidin-4,6-diol and the 4,6-dichloro-5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidine m.p. 173-176 ° C.

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Example 56

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -pyrimidin-4-yl] -benzenesulfonamide Potassium in the form of a foam. MS: (M + H) + = 551.2.

The 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -pyrimidin-4-yl] -benzenesulfonamide it was prepared starting from the hydrochloride of pyridin-3-carboxamidine pathway rac-5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -tetrahydro-1H-pyrimidin-4,6-dione and the 4,6-dichloro-5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -pyrimidine (mp 164-166 ° C).

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Example 57

A suspension of 525 mg of 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-2-yl) -pyrimidin-4-yl] -benzene-sulfonamide in 1 ml of glacial acetic acid was treated with 2.5 ml of acid 40% peracetic and slowly heated to reflux. After 2 minutes, the mixture was cooled, evaporated under reduced pressure and the residue was recrystallized with ethyl acetate. 1-oxide was obtained 2- [4- (4-tert-butyl-phenylsulfonyl-amino) -6-chloro-5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine, from p.f. 201-202 ° C (with decomposition).

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Example 58

216 mg of 1-oxide 2- [4- (4-tert-butyl-phenylsulfonylamino) -6-chloro-5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine were added to a solution of 46 mg of Na in pure ethylene glycol and the slowly obtained solution was heated at 80 ° C during night. The solution was poured into aqueous acetic acid, the precipitated with ethyl acetate, triturated with ether and separated by filtration with aspiration. 1-oxide was obtained 2- [4- (4-tert-butyl-phenylsulfonylamino) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine as an amorphous mass that was dried under high vacuum at 40 ° C. MS: (M + H) + = 567.4.

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Example 59

In analogy to Example 57, from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyrimidin-4-yl] -benzenesulfonamide and paracetic acid 1-oxide was obtained 4- [4- (4-tert-butyl-phenylsulfonylamino) -6-chloro-5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine, m.p. 247-249 ° C (with CH 2 Cl 2 and ether isopropyl).

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Example 60

In analogy to Example 58, from 1-oxide 4- [4- (4-tert-butyl-phenylsulfonylamino) -6-chloro-5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine and sodium ethylene glycol in ethylene glycol 1-oxide was obtained 4- [4- (4-tert-butyl-phenyl-sulfonylamino) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine, Like an amorphous mass MS: (M + H) + = 567.4, (M + Na) + = 589.4.

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Example 61

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2- (2-methoxy-ethyl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert-Butyl-N- [6- (2-hydroxyethoxy) -2- [2- (hydroxyethoxy) -ethyl] -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide. MS: M + = 562.

The corresponding sodium salt (prepared according to the usual methods) is a white solid that dried on high empty. The 4-tert.butyl-N- [6-chloro-2- (2-methoxy-ethyl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide it was prepared starting from the hydrochloride of methoxy-propionamidine pathway 2- (2-methoxy-ethyl) -5- (o-methoxyphenoxy) -4,6- (1H, 5H) -pyrimidinedione and the 4,6-Dichloro-2- (2-methoxy-ethyl) -5- (2-methoxyphenoxy) -pyrimidine.

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Example 62

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2-cyclopropyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [2-cyclopropyl-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide Like a foam MS: M + = 513.

The 4-tert.butyl-N- [6-chloro-2-cyclopropyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide it was prepared starting from the hydrochloride of cyclopropyl-formamidine pathway rac-2-cyclopropyl-5- (2-methoxyphenoxy) -1H-pyrimidin-4,6-dione (p-f-243-244 ° C) and the 4,6-dichloro-2-cyclopropyl-5- (2-methoxyphenoxy) pyrimidine (m.80-82 ° C).

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Example 63

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-2-ethyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzene-sulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [2-ethyl-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a foam.

The 4-tert.butyl-N- [6-chloro-2-ethyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide it was prepared starting from propionamidine hydrochloride via rac-2-ethyl-5- (2-methoxyphenoxy) -1H-pyrimidin-4,6-dione (mp 265 ° C with decomposition) and the 4,6-Dichloro-2-ethyl-5- (2-methoxyphenoxy) -pyrimidine (m.70-71 ° C).

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Example 64

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2-isopropyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -2-isopropyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid.

The 4-tert.butyl-N- [6-chloro-2-isopropyl-5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide it was prepared starting from isopropionamidine hydrochloride via rac-2-isopropyl-5- (2-methoxyphenoxy) -1,4,5,6-tetrahydro-pyrimidin-4,6-dione and the 4,6-Dichloro-2-isopropyl-5- (2-methoxyphenoxy) -pyrimidine (m.70-72 ° C).

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Example 65

In analogy to Example 50, from the 4-chloro-N- [6-chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol the 4-Chloro-N- [3- (5-fluorine-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -benzenesulfonamide, m.p. 152-154 ° C (with CH 3 CN and ether isopropyl).

The 4-chloro-N- [6-chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide (mp 169-171 ° C) was prepared from the 4,6-dichloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidine and potassium 4-chlorobenzenesulfonamide.

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Example 66

In analogy to Example 50, from the N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-trifluoromethyl-benzenesulfonamide and sodium ethylene glycol the N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -4-trifluoromethyl-benzenesulfonamide, m.p. 154-155 ° C (with isopropyl ether).

The N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-trifluoromethyl-benzenesulfonamide (mp 185-186 ° C) was prepared from the 4,6-dichloro-5-fluorine-2-methoxyphenoxy) -pyrimidine and potassium 4-trifluoromethylbenzenesulfonamide.

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Example 67

In analogy to Example 50, but at the temperature reaction temperature of 100 ° C, from the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide in the form of a solid. Sodium salt: m.p. 195-198 ° C.

The 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide was prepared from the hydrochloride of pyrimidin-2-carboxamidine pathway rac-5- (2-methoxyphenoxy) -2- (pyrimidin-2-yl) -tetrahydropyrimidin-4,6-dione and the 4,6-dichloro-5- (2-methoxyphenoxy) -2,2-bipyrimidine.

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Example 68

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-5- (3-methoxyphenoxy) -2,2-bipyrimidin-4-yl] -benzene-sulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert.butyl-M- [6- (2-hydroxyethoxy) -5- (3-methoxyphenoxy) -2,2-bipyrimidin-4-yl] -benzenesulfonamide in the form of a solid.

The 4-tert-butyl-N- [6-chloro-5- (3-methoxyphenoxy) -2,2-bipyrimidin-4-yl] -benzenesulfonamide was prepared from the rac-5- (3-methoxyphenoxy) -2- (pyrimidin-2-yl) -1,4,5,6-tetrahydro-pyrimidin-4,6-dione via 4,6-dichloro-5- (3-methoxyphenoxy) -2,2-bipyrimidinyl.

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Example 69

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -2,2-bipyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert-butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -2,2-bipyrimidin-4-yl] -benzenesulfonamide, m.p. 161-163 ° C.

The 4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -2,2-bipyrimidin-4-yl] -benzenesulfonamide (mp 225-227 ° C) was prepared from (4-fluorine-2-methoxyphenoxy) malonate diethyl via 5- (4-fluorine-2-methoxyphenoxy) -2,2-bipyrimidin-4,6-diol (decomposition point> 131 ° C) and the 4,6-dichloro-5- (4-fluorine-2-methoxyphenoxy) -2,2-bipyrimidine (mp 179-180 ° C).

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Example 70

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert.butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxy-ethoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide, m.p. 141-142 ° C (with CH 2 Cl 2 -ether isopropyl).

4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide (mp 164-
165 ° C) was prepared from diethyl (4-fluorine-2-methoxyphenoxy) malonate via rac-5- (4-fluorine-2-methoxyphenoxy) -2-methyl-1,4,5,6-tetrahydropyrimidin-4, 6-dione and 4,6-dichloro-5- (4-fluorine-2-methoxyphenoxy) -2-methylpyrimidine (mp 129-130 ° C).

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Example 71

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -benzene-sulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert-butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -benzenesulfonamide, m.p. 143-144 ° C (with CH 2 Cl 2 -ether isopropyl).

The 4-tert-butyl-N- [6-chloro-5- (4-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide (mp 146-147 ° C) was prepared from (4-fluorine-2-methoxyphenoxy) malonate diethyl via rac-5- (4-flor-2-methoxyphenoxy) -1,4,5,6-tetrahydropyrimidin-4,6-dione and the 4,6-dichloro-5- (4-fluorine-2-methoxyphenoxy) pyrimidine (m.p. 100-101 ° C).

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Example 72

In analogy to Example 50, from the N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-isopropyl-benzene-sulfonamide and sodium ethylene glycol in ethylene glycol the N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -isopropyl-benzenesulfonamide, m.p. 131-132 ° C (with isopropyl ether).

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Example 73

In analogy to Example 50, from the N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-tert.butyl-benzenesulfonamide and sodium ethylene glycol in ethylene glycol the N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -4-tert-butyl-benzenesulfonamide, m.p. 126-127 ° C (with isopropyl ether).

The N- [6-chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-isopropyl-benzenesulfonamide, m.p. 138-139 ° C, was prepared from (5-fluorine-2-methoxyphenoxy) malonate diethyl via rac-5- (5-fluorine-2-methoxyphenoxy) -tetrahydro-pyrimidin-4,6-dione, 4,6-dichloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidine (p. f. 98-100 ° C), and N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-tert.butyl-benzenesulfonamide (m.p. 163-164 ° C).

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Example 74

In analogy to Example 50, from the 4-tert-butyl-N- [6-chloro-5- (2-fluorine-6-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert-butyl-N- [5- (2-fluorine-6-methoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -benzenesulfonamide, m.p. 158-159 ° C (with CH 2 Cl 2 -ether isopropyl).

The 4-tert-butyl-N- [6-chloro-5- (2-fluorine-6-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide (mp 181-182 ° C) was prepared from 2- (2-fluorine-6-methoxyphenoxy) malonate diethyl via rac-5- (2-fluorine-6-methoxyphenoxy) -1,4,5,6-tetrahydropyrimidin-4,6-dione and the 4,6-dichloro-5- (2-fluorine-6-methoxyphenoxy) -pyrimidine (mp 78-79 ° C).

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Example 75

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-5- (3-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol the 4-tert.butyl-N- [6- (2-hydroxyethoxy) -5- (3-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, m.p. 159-161 ° C (toluene / n-hexane).

4-tert.butyl-N- [6-chloro-5- (3-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, (mp 206-
207 ° C) was prepared from rac-5- (3-methoxyphenoxy) -2- (thiophene-2-yl) -3,4,5,6-tetrahydropyrimidin-4,6-dione via 4,6-dichloro-5 - (3-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidine (mp 120-121 ° C).

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Example 76

In analogy to Example 50, from the 4-tert.butyl-N- [6-chloro-2- (2-methoxy-ethyl) -5- (3-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and sodium ethylene glycol in ethylene glycol was obtained, after the separation by chromatography on silica gel, the 4-tert-butyl-N- [6- (2-hydroxyethoxy) -2- (2-methoxy-ethyl) -5- (3-methoxy-phenoxy) -pyrimidin-4-yl] -benzenesulfonamide Y 4-tert.butyl-N- [6- (2-hydroxyethoxy) -2- [2- (2-hydroxyethoxy) -ethyl] -5- (3-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide.

The 4-tert.butyl-N- [6-chloro-2- (2-methoxy-ethyl) -5- (3-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide it was prepared from methoxypropionamidine hydrochloride via 2- (2-Methoxy-ethyl) -5- (3-methoxyphenoxy) -1,4,5,6-tetrahydro-pyrimidin-4,6-dione Y 4,6-dichloro-2- (2-chloro-ethyl) -5- (3-methoxyphenoxy) -pyrimidine.

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Example 77

In analogy to Example 50, from the p-tert.butyl-N- [6-chloro-5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide Y (S) -2,2-dimethyl-1,3-dioxolane-4-methanol sodium was obtained the (S) -4-tert.butyl-N- [6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -5- (2-methoxyphenoxy) -2-methyl-pyrimidin-4 -il] -benzenesulfonamide, m.p. 124-125 ° C (with n-hexane).

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Example 78

A solution of 1.85 g of (S) -4-tert.butyl-N- [6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -5- (2-methoxyphenoxy) -2-methylpyrimidin-4-yl ] -benzenesulfonamide in EtOH (15 ml) it was treated with 3 ml of conc. HCl. and heated to 50 ° C for 2 minutes After evaporating, the residue was extracted with ether getting the (R) -4-tert.butyl-N- [6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide in the form of a foam.

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Example 79

From the N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-tert.butyl-benzenesulfonamide and of (R) -2,2-dimethyl-1,3-dioxolan-4-methanol sodium, the (R) -4-tert.butyl-N- [5- (5-fluorine-2-methoxyphenoxy) -6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -pyrimidin-4 -il] -benzenesulfonamide (m.p.> 86 ° C). Treatment with dilute hydrochloric acid gave as a result obtaining (S) -4-tert.butyl-N-5- (fluorine-2-methoxyphenoxy) -6- (2,3-dihydroxy-propoxy) -pyrimidin-4-yl] -benzenesulfonamide, in the form of a foam.

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Example 80

From the N- [6-Chloro-5- (5-fluorine-2-methoxyphenoxy) -pyrimidin-4-yl] -4-tert-butyl-benzenesulfonamide and the sodium salt of (S) -2,2-dimethyl-1,3-dioxolan-4-methanol, the (S) -4-tert.butyl-N- [5- (5-fluorine-2-methoxyphenoxy) -6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -pyrimidin-4 -il] -benzene-sulfonamide (mp 86 ° C). Treatment with dilute HCl resulted in obtaining of (R) -4-tert.butyl-N- [5- (5-fluorine-2-methoxyphenoxy) -6- (2,3-dihydroxy-propoxy) -pyrimidin-4-yl] -benzenesulfonamide, in the form of a foam.

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Example 81

From the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (S) -2,2-dimethyl-1,3-dioxolan-4-methanol the 4-tert-butyl-N- [6 - [(S) -1,3-dioxolan-4-yl-methoxy] -5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4 -yl] -benzene sulfonamide, in the form of a foam. Treatment with dilute hydrochloric acid in dioxane resulted in obtaining the (R) -4-tert.butyl-N- [6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] - benzene sulfonamide, in the form of a foam.

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Example 82

From the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (R) -2,2-dimethyl-1,3-dioxolan-4-methanol the 4-tert-butyl-N- [6- (R) -1,3-dioxolan-4-yl-methoxy] -5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4- il] -benzenesulfonamide, and from it with HCl diluted in dioxane, the (S) -4-tert.butyl-N- [6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] - benzenesulfonamide.

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Example 83

From the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-3-yl) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (R) -2,2-dimethyl-1,3-dioxolan-4-methanol the (R) -4-tert.butyl-N- [6 - [(S) -2,2-dimethyl-1,3-dioxolan-4-yl-methoxy] -5- (2-methoxyphenoxy) -2- ( thiophen-3-yl) -pyrimidin-4-yl] -benzenesulfonamide, and from it with HCl diluted in dioxane the 4-tert.butyl-N- [6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -2- (thiophene-3-yl) -pyrimidin-4-yl] -benzenesulfonamide.

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Example 84

From the 4-tert.butyl-N- [6-chloro-5- (2-methoxyphenoxy) -2- (thiophen-3-yl) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (S) -2,2-dimethyl-1,3-dioxolan-4-methanol the (S) -4-tert.butyl-N - [(2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -5- (2-methoxy-phenoxy) -2- (thiophene-3- il) -pyrimidin-4-yl] -benzenesulfonamide, and from it with HCl diluted in dioxane the 4-tert-butyl-N- [6 - [(R) -2,3-dihydroxy-propoxy] -5- (2-methoxyphenoxy) -2- (thiophen-2-yl) -pyrimidin-4-yl] - benzenesulfonamide.

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Example 85

From the 4-tert-butyl-N- [6-chloro-2- (furan-3-yl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (S) -2,2-dimethyl-1,3-dioxolan-4-methanol the (S) -4-tert.butyl-N- [6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy] -2- (furan-3-yl) -5- (2- methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, and from it with HCl diluted in dioxane the (R) -4-tert.butyl-N- [2- (furan-3-yl) -6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide.

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Example 86

From the 4-tert-butyl-N- [6-chloro-2- (furan-3-yl) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide and the sodium salt of (R) -2,2-dimethyl-1,3-dioxolan-4-methanol the (R) -4-tert.butyl-N- [6- (2,2-dimethyl-1,3-dioxolan-4-yl-methoxy) -2- (furan-3-yl) -5- (2- methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, and from it with HCl diluted in dioxane the (S) -4-tert.butyl-N- [2- (furan-3-yl) -6- (2,3-dihydroxy-propoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] - benzenesulfonamide.

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Example 87

By reaction of the p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide and the acid 3-methyl-5-isoxazolcarboxylic in the presence of dimethyl amino pyridine and dicyclohexylcarbodiimide in methylene chloride, the ester was obtained 2- [6- (4-t-Butylbenzenesulfonamino) -5- (3-methoxy-phenoxy) -pyrimidin-4-yloxy) ethyl of the acid 3-methylisoxazol-5-carboxylic acid, in the form of a white solid.

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Example 88

In analogy with Example 87 using the acid indole-2-carboxylic acid, the ester 2- [6- (4-t-Butylbenzene-sulfonamino) -5- (3-methoxyphenoxy) pyrimidin-4-yloxy] ethyl of indole-2-carboxylic acid.

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Example 89

To a solution of 391.5 mg of 6- [2- (t-Butyl-dimethylsilyloxy) ethoxy] -5- (2-methoxyphenoxy) pyrimidin-4-ylamine in 20 ml of acetonitrile 200 mg of NaH (60%) was added and the reaction mixture was stirred for one hour at room temperature. 400 mg of the acid ethyl ester was added (2-Methoxy-5-chlorosulfonyl) phenoxyacetic. The reaction mixture was stirred for 3.5 hours at temperature. ambient, poured onto ice and extracted with ethyl acetate. The organic phase was dried and evaporated. Gel chromatography of silica with methylene chloride (methanol (120: 1) provided 175 mg of the acid ethyl ester 4- [6- [2- (t-Butyl-dimethylsilyloxy) -ethoxy] -5- (2-methoxyphenoxy) pyrimidin-4-yl-aminosulfonyl] -2-methoxyphenoxyacetic, in the form of a white foam. This compound was dissolved in 6 ml of acetonitrile and 1 ml of fluoride was added slowly at 0 ° C aqueous hydrogen (40%). The reaction mixture was stirred for 30 minutes at 0 ° C and for 90 minutes at room temperature, it was poured on ice / 2N solution of KHCO3 and extracted with methylene The organic phase was dried and evaporated and the residue chromatographed on silica gel with methylene chloride / methanol (10: 1). The acid ethyl ester was obtained 5- [N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) pyrimidin-4-yl] aminosulfonyl] -2-methoxyphenoxyacetic, in the form of a white solid.

The starting material was prepared as follow:

Approximately 105 ml of ammonia was added to a solution of 7 g of 4,6-dichloro-5- (o-methoxyphenoxy) pyrimidine in 140 ml of ethanol at -78 ° C. The reaction mixture was stirred for 15 hours at room temperature and then concentrated. He residue was distributed between ethyl acetate and water and the organic phase 6.45 g of 4-amino-6-chloro-5- (o-methoxyphenoxy) pyrimidine, in the form of white crystals.

2.3 g of the compound obtained above were added to a solution of 250 mg of sodium in 40 ml of ethylene glycol at 50 ° C. The solution was heated at 100 ° C for 12 hours, partitioned between a semisaturated aqueous solution of NH4Cl and methylene chloride and the organic phase was elaborated. 2.49 g of 2- [6-amino-5- (o-methoxyphenoxy) -4-pyrimidinyl] -1-ethanol in the form of white crystals.

To a solution of 2.5 g of the compound before obtained in 100 ml of methylene chloride, 2.74 g of dimethylamino pyridine and 3.39 g of dimethylchlorosilane from t-butyl, and the mixture was stirred at temperature ambient for 48 hours. Then another 1.35 g was added of dimethylaminopyridine and 1.65 g of dimethylchlorosilane and t-butyl and the reaction mixture was stirred for another 18 hours at room temperature. The reaction mixture is filtered, the filtrate was concentrated and the residue was partitioned between a Semisaturated aqueous solution of NH4Cl and ethyl acetate. The elaboration of the organic phase resulted in obtaining 2.78 g of 6- [2- (t-Butyl-dimethylsilyloxy] -5- (2-methoxyphenoxy) pyrimidin-4-yl-amine, in the form of a white solid.

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Example A

Tablets may be prepared, containing the following ingredients, by one of the methods Conventional:

16

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Example B

Capsules can be prepared containing the following ingredients, using one of the methods Conventional:

17

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Example C

Solutions for injection may have the following composition:

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Example D

500 mg of the compound of formula I are suspended in 3.5 ml of Myglyol 812 and 0.08 g of benzyl alcohol. This suspension is introduced into a container with a valve dosing Then 5.0 g of Freon 12 are introduced, a pressure, through the valve. The Freon dissolves by stirring in the Myglyol-benzyl alcohol mixture. This vessel spray contains about 100 doses, which can be applied individually.

Claims (19)

1. Compounds of formula 19 in where R1 means hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 to 7 carbon atoms, halogen or trifluoromethyl; R2 means hydrogen, halogen, alkoxy from 1 to 7 carbon atoms, trifluoromethyl or -OCH 2 COOR a; R 3 means hydrogen, halogen, alkyl from 1 to 7 carbon atoms, alkylthio from 1 to 7 carbon atoms, trifluoromethyl, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 7 carbon atoms or trifluoromethoxy, R 2 and R 3 together mean butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; R 4 means hydrogen, alkyl of 1 to 7 carbon atoms, cycloalkyl of 3 to 8 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 at 7 carbon atoms, alkylthio of 1 to 7 atoms of carbon-alkyl of 1 to 7 carbon atoms, hydroxy-alkyl of 1 to 7 carbon atoms, hydroxy-alkoxy of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms-alkyl of 1 to 7 carbon atoms, hydroxy-alkoxy of 1 to 7 atoms carbon-alkyl of 1 to 7 carbon atoms, hydroxy-alkoxy of 1 to 7 atoms of carbon-alkoxy of 1 to 7 carbon atoms, alkylsulfinyl of 1 to 7 carbon atoms, alkylsulfonyl of 1 to 7 carbon atoms, 2-methoxy-3-hydroxypropoxy, 2-hydroxy-3-phenyl-propyl, amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 atoms of carbon-amino-alkyl from 1 to 7 carbon atoms, dialkyl of 1 to 7 atoms of carbon-amino-alkyl from 1 to 7 carbon atoms, amino, alkyl of 1 to 7 atoms of carbon-amino, dialkyl of 1 to 7 atoms of carbon-amino, arylamino, aryl, arylthio, aryloxy, aryl-alkyl of 1 to 7 carbon atoms, where aryl represents unsubstituted phenyl or phenyl substituted with alkyl of 1 to 7 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 carbon atoms, carboxyl or halogen, heterocyclyl without replace the 2-furyl group, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl or 2-, 3- or 4-pyridyl-N-oxide, 1,2- or 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, quinazolyl or heterocyclyl as defined above, substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, halogen, aryl or aryl-alkyl of 1 to 7 atoms of carbon; R 5 hydrogen, alkyl of 1 to 7 atoms of carbon, alkanoyl of 1 to 7 carbon atoms, benzoyl, heterocyclylcarbonyl, heterocyclylmethyl, wherein heterocyclyl is chosen from 2-fury without replacing, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 1,2- or 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, quinazolyl or heterocyclyl as defined above, substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, halogen, phenyl or aryl-alkyl of 1 to 7 carbon atoms or tetrahydropyran-2-yl; R 6 to R 9 means hydrogen, halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 to 7 atoms of carbon, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or alkyloxy of 1 to 7 carbon-carbonyloxy atoms; R 7 together with R 6 or R 8 means butadienyl, methylenedioxy, ethylenedioxy or isopropylidenedioxy; Z means -O-, -S-, vinyl, -CO-, -OCHR 10 - or -SCHR 10 -; R 10 means hydrogen or alkyl of 1 to 7 carbon atoms; X and Y mean each independently among themselves, O, S or NH; YR 5 also means alkylsulfinyl of 1 at 7 carbon atoms; R a, R b, R c and R d each independently mean each other hydrogen or alkyl of 1 to 7 carbon atoms
no; or R c and R d together mean methylene, ethylene or isopropylidene; Y n means 1, 2 or 3, and you leave the same.

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2. Compounds of formula I according to claim 1, wherein R1 means hydrogen, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 to 7 carbon atoms, halogen or trifluoromethyl; R2 means hydrogen, halogen, alkoxy from 1 to 7 carbon atoms or trifluoromethyl; R 3 means hydrogen, halogen, alkyl from 1 to 7 carbon atoms, alkylthio from 1 to 7 carbon atoms, trifluoromethyl, cycloalkyl of 3 to 8 carbon atoms, alkoxy of 1 to 7 carbon atoms or trifluoromethoxy; R 2 and R 3 together mean butadienyl or methylenedioxy; R 4 means hydrogen, alkyl of 1 to 7 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 atoms of carbon, alkylthio of 1 to 7 carbon atoms, alkylthio of 1 to 7 carbon-alkyl atoms of 1 to 7 atoms of carbon, hydroxy-alkyl of 1 to 7 carbon atoms, amino-alkyl of 1 to 7 carbon atoms, alkyl of 1 to 7 atoms of carbon-amino-alkyl from 1 to 7 carbon atoms, dialkyl of 1 to 7 atoms of carbon-amino-alkyl from 1 to 7 carbon atoms, amino, alkyl of 1 to 7 atoms of carbon-amino, dialkyl of 1 to 7 atoms of carbon-amino, arylamino, aryl, arylthio, aryloxy, aryl-alkyl of 1 to 7 carbon atoms, where aryl represents unsubstituted phenyl or phenyl substituted with alkyl of 1 to 7 carbon atoms, trifluoromethyl, alkoxy of 1 to 7 carbon atoms, carboxyl or halogen, heterocyclyl without replace the 2-furyl group, 3-furyl, pyrimidinyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-, 3- or 4-pyridyl-N-oxide, 1,2- or 1,4-diazinyl, morpholino, 2-thienyl, 3-thienyl, isoxazolyl, oxazolyl, thiazolyl, imidazolyl, pyrrolyl, benzofuranyl, benzothienyl, indolyl, purinyl, quinolyl, isoquinolyl, quinazolyl or tetrahydropyran-2-yl or heterocyclyl as defined above, substituted with alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 atoms of carbon, halogen, aryl or aryl-alkyl of 1 to 7 carbon atoms; R 5 means hydrogen, alkanoyl from 1 to 7 carbon atoms, benzoyl or tetrahydropyran-2-yl; R 6 to R 9 means hydrogen, halogen, trifluoromethyl, alkyl of 1 to 7 carbon atoms, alkoxy of 1 to 7 carbon atoms, alkylthio of 1 to 7 atoms of carbon, hydroxyl, hydroxymethyl, cyano, carboxyl, formyl, methylsulfinyl, methylsulfonyl, methylsulfonyloxy or alkyloxy of 1 to 7 carbon-carbonyloxy atoms; R 7 together with R 6 or R 8 means butadienyl or -OCH2O-; Z means -O-, -S-, vinyl, -CO-, -OCHR 10 - or -SCHR 10 -; R 10 means hydrogen or alkyl of 1 to 7 carbon atoms; X and Y mean each independently among themselves, O, S or NH; R a and R b mean hydrogen; Y n means 1, 2 or 3; and you leave the same.

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3. Compounds according to claim 1 or 2, in where Z is -O-. 4. Compounds according to any one of the claims 1-3, wherein R 6 means alkoxy of 1 to 7 carbon atoms and R 7, R 8 and R 9 They mean hydrogen.

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5. Compounds according to any one of the claims 1-3, wherein R 6 and R 8 mean hydrogen, R 7 means alkoxy of 1 to 7 atoms of carbon and R 9 means halogen. 6. Compounds according to one of the claims 1-5, where R 4 is hydrogen, 2-pyrimidinyl, 2- or 3-furyl, 2- or 3-thienyl, morpholino or p-methoxyphenyl. 7. Compounds according to any one of the claims 1-6, wherein YR 5 is hydroxyl, alkoxysulfinyl of 1 to 7 carbon atoms or furoyloxy. 8. The compounds according to claim 3: p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidin] benzenesulfonamide, N- [6- (hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-tolyloxy) -4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-chlorophenyloxy) -4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-chlorophenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5-phenoxy-4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (p-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-ethoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, p- (2,2-dimethylpropyl) -N- [6- (2-hydroxyethoxy) -5- (o-methoxy-phenoxy) -4-pyrimidinyl] -benzenesulfonamide, p-isopropyl-N- [6- (2-hydroxyethoxy) -2-methyl-5- (m-methoxyphenoxy) -4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-phenyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -6- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -o-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (2,4,6-trichlorophenoxy) -4-pyrimidinyl] -2,4-xylenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5 - [(2-methoxy-p-tolyl) -oxy] -4-pyrimidinyl] -benzenesulfonamide, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2- (trifluoromethyl) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2- (trifluoromethyl) -4-pyrimidinyl] -benzenesulfonamide, N- [5- (1,3-benzodioxol-5-yloxy) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p-tert-butylbenzenesulfonamide, N- [5- (1,3-benzodioxol-5-yloxy) -6- (2-hydroxyethoxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -o-methoxybenzenesulfonamide, p-tert-butyl-N- [6- (4-hydroxybutyloxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (2-naphthyloxy) -4-pyrimidinyl] -p-isopropylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (2-naphthyloxy) -4-pyrimidinyl] -p-tert-butylbenzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-propyl-4-pyrimidinyl] -p-isopropylbenzenesulfonamide, p-tert-butyl-N- [6-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-propyl-4-pyrimidinyl] -benzenesulfonamide, α, α, α-trifluor-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-toluenesulfonamide, p-chloro-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p- (trifluoromethoxy) benzenesulfonamide, o-ethyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -p-toluenesulfonamide, N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -2-naphthylsulfonamide, p-tert-butyl-N- [6- (3-hydroxypropoxy) -5- (o-methoxyphenoxy) -2-methyl-4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5 - [(o-methylthio) -phenoxy] -4-pyrimidinyl] -benzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -2-phenyl-4-pyrimidinyl] -benzenesulfonamide, N- [2-amino-6- (2-hydroxyethoxy) -5- (o-methoxyphenoxy) -4-pyrimidinyl] -p-t-butylbenzenesulfonamide, p-t-butyl-N- [6- (2-hydroxyethoxy) -2-methyl-5- [o- (methylthio) phenoxy] -4-pyrimidinyl] -benzenesulfonamide Y p-t-butyl-N- [6- (2-hydroxyethoxy) -2-methyl-5- [o- (R, S-methylsulfinyl) phenoxy] -4-pyrimidinyl] -benzenesulfonamide.

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9. The compounds according to claim 3: 4-tert-butyl-N- [5- (2-chloro-5-methoxyphenoxy) -6- (2-hydroxy-ethoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [5- (2-chloro-5-methoxyphenoxy) -6- (2- (3-furoyl-oxy) ethoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (thiophene-3-yl) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [2- (furan-2-yl) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [2- (furan-3-yl) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyridin-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyridin-4-yl) -pyridin-4-yl] -benzenesulfonamide, 4-tert-butyl-N-, 6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -2- (pyridin-3-yl) -pyrimidin-4-yl] -benzenesulfonamide, 1-oxide 2- [4- (4-tert-Butyl-phenylsulfonylamino) -6- (2-hydroxy-ethoxy) -5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine, 1-oxide 4- [4- (4-tert-Butyl-phenylsulfonylamino) -6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-2-yl] -pyridine, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -2- [2- (2-hydroxyethoxy) -ethyl] -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfone-
measure, 4-tert-butyl-N- [2-cyclopropyl-6- (2-hydroxyethoxy) -5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [2-ethyl-6- (2-hydroxyethoxy) -5- (2-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -2-isopropyl-5- (2-methoxy-phenoxy) -pyrimidin-4-yl] -benzenesulfonamide, N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -4-trifluoromethyl-benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (3-methoxyphenoxy) -2,2'-bipyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -2,2, -bipyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxy-ethoxy) -2-methyl-pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [5- (4-fluorine-2-methoxyphenoxy) -6- (2-hydroxy-ethoxy) -pyrimidin-4-yl] -benzenesulfonamide, N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -4-isopropyl-benzenesulfonamide, N- [5- (5-Fluoro-2-methoxyphenoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -4-tert-butyl-benzenesulfonamide, 4-tert-butyl-N- [5- (2-fluorine-6-methoxy) -6- (2-hydroxyethoxy) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -5- (3-methoxyphenoxy) -2- (thiophene-2-yl) -pyrimidin-4-yl] -benzenesulfonamide, 4-tert-butyl-N- [6- (2-hydroxyethoxy) -2- (2-methoxy-ethyl) -5- (3-methoxyphenoxy) -pyrimidin-4-yl] -benzenesulfonamide, ester 2- [6- (4-t-Butylbenzenesulfonamino) -5- (3-methoxy-phenoxy) pyrimidin-4-yloxy] -ethyl of the acid 3-methylisoxazol-5-carboxylic acid, ester 2- [6- (4-t-Butylbenzenesulfonamino) -5- (3-methoxy-phenoxy) pyrimidin-4-yloxy] -ethyl of indole-2-carboxylic acid, ethyl acid ester 5- [N- [6- (2-Hydroxyethoxy) -5- (2-methoxy-phenoxy) pyrimidin-4-yl] aminosulfonyl] -2-methoxyphenoxyacetic acid.

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10. Compound according to claim 1 characterized in that it is (RS) -4-tert-butyl-N- [5- (2-chloro-5-methoxy-phenoxy) -2-ethyl-6- (2-methylsulfinyl-ethoxy ) -pyrimidin-4-yl] -benzenesulfonamide. 11. Compound according to claim 1 characterized in that it is (RS) -N- [5- (2-Chloro-5-methoxy-phenoxy) -6- (2-methylsulfinyl-ethoxy) -pyrimidin-4-yl] -1 , 3-benzodioxol-5-sulfonamide. 12. Compound according to claim 1 characterized in that it is 4-tert-butyl-N- [6- (2-hydroxy-ethoxy) -5- (2-methoxy-phenoxy) -2- (pyrimidin-2-yl) - pyrimidin-4-yl] -benzene-sulfonamide. 13. Compounds according to claim 1 or 2, in where Z is vinyl. 14. The compounds according to claim 13: acetate 2 - [[5 - [(E / Z) -styryl] -6-p-toluenesulfonamido-4-pyrimidin] oxy] ethyl, N- [6- (2-hydroxyethoxy) -5 - [(E / Z) -styryl] -4-pyrimidinyl] -p-toluenesulfonamide.

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15. Compounds of formula twenty where R 1 -R 4, R 6 -R 9 and Z they have the meaning given in claim 1 and Hal means halogen

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16. The compounds of the claims 1-14 for use as medications. 17. Pharmaceutical preparations containing a compound according to claims 1-14 and usual vehicles and adjuvants. 18. Use of compounds according to the claims 1-14 as active ingredients for the manufacture of medicines intended for the treatment of diseases associated with endothelin activities, especially diseases circulatory, such as hypertension, ischemia, spasms vascular and angina pectoris.

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19. Process for obtaining compounds of claims 1-14, characterized in that: a) A compound of is reacted formula: twenty-one where R 1 -R 4, R 6 -R 9 and Z they have the meaning given in claim 1 and Hal is halogen, with a compound of formula 22 wherein X, Y, n, R a, R b and R 5 have the meaning given in claim 1 and M represents an alkali metal; or good

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b) A compound of is reacted formula: 2. 3 where R 1 -R 5, R a, R b, X, Y and n have the meaning given above, with a compound of formula: 24 where R 6 -R 8 have the meaning given more above, Q is aryl and A - is an anion, or good

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c) A compound of the formula is hydrogenated: 25 where R 1 -R 9, R a, R b, X, Y and n have the meaning given above, or good

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d) A compound of is reacted formula: 26 with a compound of formula: 27 where R 1 -R 9, R a, R b, X, Y, Z and n they have the meaning given above, and if desired, they are modified the substituents present in the compound of formula I obtained and / or the compound of formula I obtained is converted into a Salt.